EP2616080A1 - Analogues de carba-nucléosides substitués par 2'-fluoro pour traitement antiviral - Google Patents

Analogues de carba-nucléosides substitués par 2'-fluoro pour traitement antiviral

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Publication number
EP2616080A1
EP2616080A1 EP11761204.4A EP11761204A EP2616080A1 EP 2616080 A1 EP2616080 A1 EP 2616080A1 EP 11761204 A EP11761204 A EP 11761204A EP 2616080 A1 EP2616080 A1 EP 2616080A1
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EP
European Patent Office
Prior art keywords
alkyl
independently
formula
aryl
alkynyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP11761204.4A
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German (de)
English (en)
Inventor
Michael O' Neil Hanrahan Clarke
Choung U. Kim
Willard Lew
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Gilead Sciences Inc
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Gilead Sciences Inc
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Publication of EP2616080A1 publication Critical patent/EP2616080A1/fr
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    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C07H21/02—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with ribosyl as saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
    • C07H7/06—Heterocyclic radicals

Definitions

  • the invention relates generally to compounds with antiviral activity, more particularly nucleosides active against Orthomyxoviridae virus infections.
  • Influenza viruses of the Orthomyxoviridae family that belong to the genera A and B are responsible for seasonal flu epidemics each year, which cause acute contagious respiratory infections. Children, the old, and people with chronic diseases are at high risk to develop severe complications that lead to high morbidity and mortality rates (Memoli et al, Drug Discovery Today 2008, 13, 590- 595).
  • type A viruses are the most virulent human pathogens that cause the most severe disease, can be transmitted to other species, and give rise to human influenza pandemics.
  • the recent human influenza outbreak of the aggressive porcine A/H1N1 strain in 2009 has emphasized the need for novel antiviral therapeutics.
  • anti-influenza therapeutics are now available and others are under development (Hedlund, et al., Viruses 2010, 2, 1766-1781).
  • M2 ion channel blockers amantadine and rimantadine and the neuraminidase inhibitors oseltamivir and zanamivir.
  • Attorney Docket No. 843.PF resistance has developed to all of these medications. Therefore there is a continuing need for novel anti-influenza therapeutics.
  • Ribosides of pyrrolo[l,2-f][l ,2,4]triazinyl, imidazo[l ,5-f][l,2,4]triazinyl, imidazo[l,2-f][l ,2,4]triazinyl, and [l,2,4]triazolo[4,3-fj[l,2,4]triazinyl nucleobases with antiviral, anti-HCV, and anti-RdRp activity have been disclosed by Babu, Y. S., WO2008/089105 and WO2008/141079; Cho, et al., WO2009/132123 and Francom, et al. WO2010/002877.
  • the invention also comprises compounds of Formula I that inhibit viral nucleic acid polymerases, particularly Orthomyxoviridae RNA-dependent RNA polymerase (RdRp), rather than cellular nucleic acid polymerases.
  • RdRp Orthomyxoviridae RNA-dependent RNA polymerase
  • Compounds of Formula I are useful for treating Orthomyxoviridae infections in humans and other animals.
  • a method for treating a Orthomyxoviridae infection in a mammal in need thereof comprising administering a therapeutically effective amount of a
  • each R 1 is H or halogen
  • each R is halogen
  • each R 3 or R 5 is independently H, OR a , N(R a ) 2 , N 3 , CN, N0 2 , S(0) n R a , halogen, (Ci-Cg)alkyl, (C 4 -C 8 )carbocyclylalkyl, (Q-C ⁇ substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -Cg)substituted alkenyl, (C 2 -C 8 )alkynyl or (C 2 -C )substituted alkynyl;
  • each n is independently 0, 1, or 2;
  • each Y or Y 1 is, independently, O, S, NR, ⁇ (OXR), N(OR), " ⁇ lOXOR), or N-NR 2 ;
  • W 1 and W 2 when taken together, are -Y 3 (C(R y ) 2 ) 3 Y 3 -; or one of W 1 or W 2 together with either R 3 is -Y 3 - and the other of W 1 or W2 is Formula la; or W 1 and W2 are each, independently, a u of the Formula la:
  • each Y 2 is independently a bond, O, CR 2 , NR, + N(0)(R), N(OR), + N(0)(OR), N-NR 2 , S, S-S, S(O), or S(0) 2 ;
  • each Y is independently O, S, or NR;
  • M2 is 0, 1 or 2; Attorney Docket No. 843.PF each R x is inde endently R y or the formula:
  • each Mia, Ml c, and Mid is independently 0 or 1 ;
  • M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12;
  • each R is independently H, (Q-Q) alkyl, (C]-C 8 ) substituted alkyl, (C 2 - Cg)alkenyl, (C 2 -C 8 ) substituted alkenyl, (C 2 -Cg) alkynyl, (C 2 -C 8 ) substituted alkynyl, C 6 -C 2 o aryl, C 6 -C 2 o substituted aryl, C 2 -C 20 heterocyclyl, C 2 -C 20 substituted
  • heterocyclyl arylalkyl or substituted arylalkyl
  • W 3 is W 4 or W 5 ;
  • W 4 is R, -0( ⁇ 3 ⁇ 4 -C(Y J )W 5 , -S0 2 R y , or -S0 2 W 5 ; and
  • W 5 is a carbocycle or a heterocycle wherein W 5 is independently substituted with 0 to 3 R y groups;
  • each R 9 or R 10 is independently H, halogen, NR n R 12 , N(R n )OR n ,
  • each R , R , R , R or R is, independently, optionally substituted with one or more halo, hydroxy, CN, N 3 , N(R a ) 2 or OR a ; and wherein one or more of the non-terminal carbon atoms of each said (C 1 -C 8 )alkyl may be optionally replaced with -0-, -S- or - NR a -.
  • the method comprises administering a therapeutically effective amount of a racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate or solvate of a compound of Formula I or a pharmaceutically acceptable salt or ester thereof to a mammal in need thereof.
  • the method comprises treating a Orthomyxoviridae infection in a mammal in need thereof by administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or ester thereof.
  • the Orthomyxoviridae infection is a Influenzavirus A infection.
  • the method comprises treating a Orthomyxoviridae infection in a mammal in need thereof by administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or ester thereof.
  • the Orthomyxoviridae infection is a Influenzavirus A infection.
  • the method comprises treating a Orthomyxoviridae infection in a mammal in need thereof by administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or ester thereof.
  • the Orthomyxoviridae infection is a Influenzavirus A infection.
  • Orthomyxoviridae infection is a Influenzavirus B infection. In another aspect of this embodiment, the Orthomyxoviridae infection is a Influenzavirus C infection.
  • the method comprises treating a Orthomyxoviridae infection in a mammal in need thereof by administering a therapeutically effective amount of a pharmaceutical composition comprising an effective amount of a Formula I compound, or a pharmaceutically acceptable salt or ester thereof, in combination with a pharmaceutically acceptable diluent or carrier.
  • a pharmaceutical composition comprising an effective amount of a Formula I compound, or a pharmaceutically acceptable salt or ester thereof, in combination with a pharmaceutically acceptable diluent or carrier.
  • Attorney Docket No. 843.PF the Orthomyxoviridae infection is a Influenza viras A infection.
  • the Orthomyxoviridae infection is a Influenza virus B infection.
  • the Orthomyxoviridae infection is a Influenza virus C infection.
  • the method comprises treating a Orthomyxoviridae infection in a mammal in need thereof by administering a therapeutically effective amount of a pharmaceutical composition comprising an effective amount of a Formula I compound, or a pharmaceutically acceptable salt or ester thereof, in combination with at least one additional therapeutic agent.
  • the Orthomyxoviridae infection is a Influenza virus A infection.
  • the Orthomyxoviridae infection is a Influenza viras B infection.
  • the Orthomyxoviridae infection is a Influenza viras C infection.
  • the present application provides for a method of inhibiting a Orthomyxoviridae RNA-dependent RNA polymerase, comprising
  • the Orthomyxoviridae RNA-dependent RNA polymerase is a Influenza viras A RNA-dependent RNA polymerase.
  • the Orthomyxoviridae RNA-dependent RNA polymerase is a Influenza virus B RNA-dependent RNA polymerase.
  • the Orthomyxoviridae RNA-dependent RNA polymerase is a Influenza virus C RNA-dependent RNA polymerase.
  • a compound of Formula I or a pharmaceutically acceptable salt, solvate, and/or ester thereof to treat a viral infection caused by a Orthomyxoviridae viras.
  • the present application provides for combination pharmaceutical agent comprising:
  • a) a first pharmaceutical composition comprising a compound of Formula I; or a pharmaceutically acceptable salt, solvate, or ester thereof; and Attorney Docket No. 843.PF b) a second pharmaceutical composition comprising at least one additional therapeutic agent active against infectious Orthomyxoviridae viruses.
  • the additional therapeutic agent is a viral haemagglutinin inhibitor, a viral neuramidase inhibitor, a M2 ion channel inhibitor, a Orthomyxoviridae RNA-dependent RNA polymerase inhibitor or a sialidase.
  • the additional therapeutic agent is selected from the group consisting of ribavirin, oseltamivir, zanamivir, laninamivir, peramivir,
  • the present application provides for a method of treating a Orthomyxoviridae virus infection in a patient, comprising administering to said patient a therapeutically effective amount of a compound of Formula I; or a pharmaceutically acceptable salt, solvate, and/or ester thereof.
  • the Orthomyxoviridae virus is Influenza virus A.
  • the Orthomyxoviridae virus is Influenza virus B.
  • the Orthomyxoviridae virus is Influenza virus C.
  • the present application provides for a method of treating a Orthomyxoviridae virus infection in a patient, comprising administering to said patient a therapeutically effective amount of a compound of Formula I; or a pharmaceutically acceptable salt, solvate, and/or ester thereof; and at least one additional therapeutic agent.
  • the additional therapeutic agent is selected from the group consisting of ribavirin, oseltamivir, zanamivir, laninamivir, peramivir, amantadine, rimantadine, CS-8958, favipiravir, AVI-7100, alpha-1 protease inhibitor and DAS181.
  • the invention also provides processes and novel intermediates disclosed herein which are useful for preparing Formula I compounds of the invention.
  • a method of treating a Orthomyxoviridae infection in a mammal in need thereof comprising administering a therapeutically effective amount of a compound of Formula I represented by Formula II:
  • R 1 is H.
  • R 6 is H, CN, halogen, (Ci-Cg)alkyl, (Ci-C8)substituted alkyl,
  • R 6 is H, CN, methyl, ethenyl, or ethynyl. In another aspect of this embodiment, R 6 is H. In another aspect of this embodiment, Attorney Docket No. 843.PF R 6 is CN. In another aspect of this embodiment, R 6 is methyl. In another aspect of this embodiment, R 6 is ethenyl. In another aspect of this embodiment, R 6 is ethynyl.
  • R 10 is H, halogen, CN, CHO, or optionally substituted heteroaryl. In another aspect of this embodiment, R 10 is H, halogen or CN. In another aspect of this embodiment, R 10 is H. In another aspect of this embodiment, R 10 is halogen. In another aspect of this embodiment, R 8 is NR 11 R 12. In another aspect of this embodiment, R 8 is NH 2 . In another aspect of this embodiment, R 8 is OR 11 . In another aspect of this embodiment, R 8 is OH. In another aspect of this embodiment, R 9 is H. In another aspect of this embodiment, R 9 is NR n R 12 . In another aspect of this embodiment, R 9 is NH 2 .
  • R a is H.
  • R 7 is H. In another aspect of this embodiment, R is
  • R 1 is F.
  • R 6 is H, CN, halogen, (C 1 -C 8 )alkyl, (Ci-Cg)substituted alkyl,
  • R 6 is H, CN, methyl, ethenyl, or ethynyl. In another aspect of this embodiment, R 6 is H. In another aspect of this embodiment, R 6 is CN. In another aspect of this embodiment, R 6 is methyl. In another aspect of this embodiment, R 6 is ethenyl. In another aspect of this embodiment, R 6 is ethynyl.
  • R 10 is H, halogen, CN, CHO, or optionally Attorney Docket No. 843.PF substituted heteroaryl.
  • R is H, halogen or CN.
  • R 10 is H.
  • R 10 is halogen.
  • R 8 is NR u R 12 .
  • R 8 is NH 2 .
  • R 8 is OR 11 .
  • R is OH.
  • R is H.
  • R 9 is NR n R 12 .
  • R 9 is N3 ⁇ 4.
  • R a is H.
  • R 7 is H. In another aspect of this embodiment, R 7 is
  • each R 1 and R 6 is H.
  • R 10 is H, halogen, CN, CHO, or optionally substituted heteroaryl.
  • R 10 is H, halogen or CN.
  • R 10 is H.
  • R 10 is halogen.
  • R 8 is NR n R 12 .
  • R 8 is NH 2 .
  • R 8 is OR 11 .
  • R 8 is OH.
  • R 9 is H.
  • R 11 or R u is independently H, (d- Cg)alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 4 -C 8 )carbocyclylalkyl, optionally
  • R n and R 12 taken together with a nitrogen to which they are both attached, form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with - 0-, -S- or -NR a -. Therefore, by way of example and not limitation, the moiety - NR n R 1
  • each R 3 , R 5 , R 6 , R 11 or R 12 is, independently, (C 1 -C 8 )alkyl, (C 2 -Cg)alkenyl, (C 2 -C 8 )alkynyl or aryl(Ci-C 8 )alkyl, wherein said (Ci-C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl or aryl(Ci-C 8 )alkyl are, independently, optionally substituted with one or more halo, hydroxy, CN, N 3 , N(R a ) 2 or OR a .
  • R 3 , R 4 , R 5 , R 6 , R 11 or R 12 could represent moieties such as -CH(NH 2 )CH 3 , -CH(OH)CH2CH3, - CH(NH 2 )CH(CH 3 ) 2 , -CH 2 CF 3 , -(CH 2 ) 2 CH(N 3 )CH 3 , -(CH 2 ) 6 NH 2 and the like.
  • R 3 , R 5 , R 6 , R 11 or R 12 is (Ci-Cg)alk l wherein one or more of the non-terminal carbon atoms of each said (Ci-C 8 )alkyl may be optionally replaced with -0-, -S- or -NR a -. Therefore, by way of example and not Attorney Docket No. 843.PF limitation, R 3 , R 5 , R 6 , R 11 or R 12 could represent moieties such as -CH 2 OCH 3 , -
  • a compound of the invention or "a compound of Formula I” means a compound of Formula I or a pharmaceutically acceptable salt, thereof.
  • a compound of Formula (number) means a compound of that formula and pharmaceutically acceptable salts, thereof.
  • Alkyl is hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms.
  • an alkyl group can have 1 to 20 carbon atoms (i.e, C 1 -C 2 0 alkyl), 1 to 8 carbon atoms (i.e. , Ci-Cg alkyl), or 1 to 6 carbon atoms (i.e. , Ci-C 6 alkyl).
  • alkyl groups include, but are not limited to, methyl (Me, -C3 ⁇ 4), ethyl (Et, -CH 2 CH 3 ), 1 -propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, -CH(CH 3 ) 2 ), 1 -butyl (n-Bu, n-butyl, -CH 2 CH2CH 2 CH3), 2-methyl-l -propyl (i-Bu, i- butyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl Attorney Docket No. 843.PF (t-Bu, t-butyl, -C(CH 3 ) 3 ), 1 -pentyl (n-pentyl, -CH 2 CH 3
  • Alkoxy means a group having the formula -O-alkyl, in which an alkyl group, as defined above, is attached to the parent molecule via an oxygen atom.
  • the alkyl portion of an alkoxy group can have 1 to 20 carbon atoms (i.e., Ci-C 20 alkoxy), 1 to 12 carbon atoms(z ' .e., Q-Cn alkoxy), or 1 to 6 carbon atoms(z ' .e., Ci-C 6 alkoxy).
  • alkoxy groups include, but are not limited to, methoxy (-0-CH 3 or -OMe), ethoxy (-OCH 2 CH 3 or -OEt), t-butoxy (-0-C(CH 3 ) 3 or -OtBu) and the like.
  • Haloalkyl is an alkyl group, as defined above, in which one or more hydrogen atoms of the alkyl group is replaced with a halogen atom.
  • the alkyl portion of a haloalkyl group can have 1 to 20 carbon atoms (i.e., Ci-C 2 o haloalkyl), 1 to 12 carbon atoms(z ' .e., Cj-C 12 haloalkyl), or 1 to 6 carbon atoms( .e., Ci-C 6 alkyl).
  • suitable haloalkyl groups include, but are not limited to, -CF 3 , -CHF 2 , -CFH 2 , -CH 2 CF 3 , and the like.
  • Alkenyl is a hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp double bond.
  • an alkenyl group can have 2 to 20 carbon atoms (i.e., C 2 -C 20 alkenyl), 2 to 8 carbon atoms (i.e., C 2 -Cg alkenyl), or 2 to 6 carbon atoms (i.e., C 2 -C 6 alkenyl).
  • PF "Alkynyl” is a hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp triple bond.
  • an alkynyl group can have 2 to 20 carbon atoms ⁇ i.e., C 2 -C 20 alkynyl), 2 to 8 carbon atoms ⁇ i.e., C 2 -Cg alkyne,), or 2 to 6 carbon atoms ⁇ i.e., C 2 -C 6 alkynyl).
  • alkynyl groups examples include, but are not limited to, acetylenic
  • Alkylene refers to a saturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane.
  • an alkylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
  • Typical alkylene radicals include, but are not limited to, methylene (-CH 2 -), 1,1 -ethyl (-CH(C3 ⁇ 4)-), 1,2-ethyl (-C3 ⁇ 4C3 ⁇ 4-), 1,1 -propyl (-CH(CH 2 CH 3 )-), 1,2-propyl (-CH 2 CH(CH 3 )-), 1,3-propyl (-CH 2 CH 2 CH 2 -), 1,4-butyl (-CH 2 CH 2 CH 2 CH 2 -), and the like.
  • alkenylene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene.
  • alkenylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
  • Alkynylene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne.
  • an alkynylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
  • Typical alkynylene radicals include, but are not limited to, acetylene (-G -), propargyl (-CH 2 C ⁇ C-), and 4-pentynyl (-CH 2 CH 2 CH 2 C ⁇ C-).
  • Ammonia refers generally to a nitrogen radical which can be considered a derivative of ammonia, having the formula -N(X) 2 , where each "X" is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or Attorney Docket No. 843.PF unsubstituted heterocyclyl, etc.
  • the hybridization of the nitrogen is approximately sp 3 .
  • Nonlimiting types of amino include -NH 2 , -N(alkyl) 2 , -NH(alkyl), -N(carbocyclyl) 2 , - NH(carbocyclyl), -N(heterocyclyl) 2 , -NH(heterocyclyl), -N(aryl) 2 , -NH(aryl), - N(alkyl)(aryl), -N(alkyl)(heterocyclyl), -N(carbocyclyl)(heterocyclyl), - N(aryl)(heteroaryl), -N(alkyl)(heteroaryl), etc.
  • alkylamino refers to an amino group substituted with at least one alkyl group.
  • Nonlimiting examples of amino groups include -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -NH(CH 2 CH 3 ), - N(CH 2 CH 3 ) 2 , -NH(phenyl), - N(phenyl) 2 , -NH(benzyl), -N(benzyl) 2 , etc.
  • Substituted alkylamino refers generally to alkylamino groups, as defined above, in which at least one substituted alkyl, as defined herein, is attached to the amino nitrogen atom.
  • Non-limiting examples of substituted alkylamino includes -NH(alkylene-C(0)-OH), -NH(alkylene-C(0)-0-alkyl), - N(alkylene-C(0)-OH) 2 , -N(alkylene-C(0)-0-alkyl) 2 , etc.
  • Aryl means an aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms.
  • Typical aryl groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), substituted benzene, naphthalene, anthracene, biphenyl, and the like.
  • Arylalkyl refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with an aryl radical.
  • Typical arylalkyl groups include, but are not limited to, benzyl, 2- phenylethan-l-yl, naphthylmethyl, 2-naphthylethan-l-yl, naphthobenzyl,
  • the arylalkyl group can comprise 7 to 20 carbon atoms, e.g., the alkyl moiety is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.
  • Arylalkenyl refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, but also an sp 2 carbon atom, is replaced with an aryl radical.
  • the aryl portion of the arylalkenyl can include, for example, any of the aryl groups disclosed herein, and the alkenyl portion of the arylalkenyl can include, for example, any of the alkenyl groups disclosed herein.
  • Attorney Docket No. 843.PF The arylalkenyl group can comprise 8 to 20 carbon atoms, e.g., the alkenyl moiety is 2 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.
  • Arylalkynyl refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, but also an sp carbon atom, is replaced with an aryl radical.
  • the aryl portion of the arylalkynyl can include, for example, any of the aryl groups disclosed herein, and the alkynyl portion of the arylalkynyl can include, for example, any of the alkynyl groups disclosed herein.
  • the arylalkynyl group can comprise 8 to 20 carbon atoms, e.g., the alkynyl moiety is 2 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.
  • substituted in reference to alkyl, alkylene, aryl, arylalkyl, alkoxy, heterocyclyl, heteroaryl, carbocyclyl, etc. , for example, "substituted alkyl"
  • substituted alkylene means alkyl, alkylene, aryl, arylalkyl, heterocyclyl, carbocyclyl respectively, in which one or more hydrogen atoms are each independently replaced with a non-hydrogen substituent.
  • Alkylene, alkenylene, and alkynylene groups may also be similarly substituted. Unless otherwise indicated, when the term "substituted" is used in conjunction with groups such as arylalkyl, which have two or more moieties capable of substitution, the substituents can be attached to the aryl moiety, the alkyl moiety, or both.
  • prodrug refers to any compound that when administered to a biological system generates the drug substance, i.e., active ingredient, as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), photolysis, Attorney Docket No. 843.PF and/or metabolic chemical reaction(s).
  • a prodrug is thus a covalently modified analog or latent form of a therapeutically active compound.
  • Heteroalkyl refers to an alkyl group where one or more carbon atoms have been replaced with a heteroatom, such as, O, N, or S.
  • a heteroatom e.g., O, N, or S
  • the resulting heteroalkyl groups are, respectively, an alkoxy group (e.g., -OCH3, etc.), an amine (e.g., -NHCH 3 , -N(CH 3 ) 2 , etc.), or a thioalkyl group (e.g., -SCH3).
  • the resulting heteroalkyl groups are, respectively, an alkyl ether (e.g., -CH 2 CH 2 -O-CH3, etc.), an alkyl amine (e.g.,
  • a terminal carbon atom of the alkyl group is replaced with a heteroatom (e.g., O, N, or S)
  • the resulting heteroalkyl groups are, respectively, a hydroxyalkyl group (e.g., -CH 2 CH 2 -OH), an aminoalkyl group (e.g., -C3 ⁇ 4NH 2 ), or an alkyl thiol group (e.g., -CH 2 CH 2 -SH).
  • a heteroalkyl group can have, for example, 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
  • a Ci-C 6 heteroalkyl group means a heteroalkyl group having 1 to 6 carbon atoms.
  • Heterocycle or “heterocyclyl” as used herein includes by way of example and not limitation those heterocycles described in Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds, A Series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566.
  • “heterocycle” includes a "carbocycle” as defined herein, wherein one or more Attorney Docket No. 843. PF (e.g. 1, 2, 3, or 4) carbon atoms have been replaced with a heteroatom (e.g. O, N, or S).
  • the terms “heterocycle” or “heterocyclyl” includes saturated rings, partially
  • heterocyclyls include, for example, heterocyclic rings substituted with any of the substituents disclosed herein including carbonyl groups.
  • a non-limiting example of a carbonyl substituted heterocyclyl is:
  • heterocycles include by way of example and not limitation pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,
  • carbon bonded heterocycles are bonded Attorney Docket No. 843.PF at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline.
  • carbon bonded heterocycles include 2-pyridyl, 3 -pyridyl, 4- pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.
  • nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3 -imidazoline, pyrazole, pyrazolone, 2- pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, lH-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or ⁇ -carboline.
  • nitrogen bonded heterocycles include 1- aziridyl, 1-azetedyl, 1-pyrrolyl, 1 -imidazolyl, 1-pyrazolyl, and 1-piperidinyl.
  • Heterocyclylalkyl refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with a heterocyclyl radical (i.e., a heterocyclyl-alkylene- moiety).
  • Typical heterocyclyl alkyl groups include, but are not limited to heterocyclyl-CH 2 -, 2-
  • heterocyclyl (heterocyclyl)ethan-l-yl, and the like, wherein the "heterocyclyl” portion includes any of the heterocyclyl groups described above, including those described in Principles of Modern Heterocyclic Chemistry.
  • the heterocyclyl group can be attached to the alkyl portion of the heterocyclyl alkyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable.
  • the heterocyclyl alkyl group comprises 3 to 20 carbon atoms, e.g., the alkyl portion of the arylalkyl group is 1 to 6 carbon atoms and the heterocyclyl moiety is 2 to 14 carbon atoms.
  • heterocyclylalkyls include by way of example and not limitation 5-membered sulfur, oxygen, and/or Attorney Docket No. 843.PF nitrogen containing heterocyeles such as thiazolylmethyl, 2-thiazolylethan-l-yl, imidazolylmethyl, oxazolylmefhyl, thiadiazolylmethyl, etc., 6-membered sulfur, oxygen, and/or nitrogen containing heterocyeles such as piperidinylmethyl,
  • Heterocyclylalkenyl refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp carbon atom, but also a sp carbon atom, is replaced with a heterocyclyl radical (i.e., a heterocyclyl- alkenylene- moiety).
  • the heterocyclyl portion of the heterocyclyl alkenyl group includes any of the heterocyclyl groups described herein, including those described in Principles of Modern Heterocyclic Chemistry, and the alkenyl portion of the
  • heterocyclyl alkenyl group includes any of the alkenyl groups disclosed herein.
  • the heterocyclyl group can be attached to the alkenyl portion of the heterocyclyl alkenyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable.
  • the heterocyclyl alkenyl group comprises 4 to 20 carbon atoms, e.g., the alkenyl portion of the heterocyclyl alkenyl group is 2 to 6 carbon atoms and the heterocyclyl moiety is 2 to 14 carbon atoms.
  • Heterocyclylalkynyl refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, but also an sp carbon atom, is replaced with a heterocyclyl radical (i.e., a heterocyclylalkynyl ene- moiety).
  • the heterocyclyl portion of the heterocyclyl alkynyl group includes any of the heterocyclyl groups described herein, including those described in Principles of Modern Heterocyclic Chemistry, and the alkynyl portion of the
  • heterocyclyl alkynyl group includes any of the alkynyl groups disclosed herein.
  • the heterocyclyl group can be attached to the alkynyl portion of the heterocyclyl alkynyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable.
  • the heterocyclyl alkynyl group comprises 4 to 20 carbon atoms, e.g., the alkynyl portion of the heterocyclyl alkynyl group is 2 to 6 carbon atoms and the heterocyclyl Attorney Docket No. 843.PF moiety is 2 to 14 carbon atoms.
  • Heteroaryl refers to an aromatic heterocyclyl having at least one heteroatom in the ring.
  • suitable heteroatoms which can be included in the aromatic ring include oxygen, sulfur, and nitrogen.
  • suitable heteroaryl rings include all of those aromatic rings listed in the definition of
  • heterocyclyl including pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazyl, pyrimidyl, pyrazyl, etc.
  • Carbocycle or “carbocyclyl” refers to a saturated (i.e., cycloalkyl), partially unsaturated (e.g., cycloakenyl, cycloalkadienyl, etc.) or aromatic ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle.
  • Monocyclic carbocycles have 3 to 7 ring atoms, still more typically 5 or 6 ring atoms.
  • Bicyclic carbocycles have 7 to 12 ring atoms, e.g., arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system, or spiro-fused rings.
  • Non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l- enyl, 1 -cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-l-enyl, 1- cyclohex-2-enyl, l-cyclohex-3-enyl, and phenyl.
  • Non-limiting examples of bicyclo carbocycles includes naphthyl, tetrahydronapthalene, and decaline.
  • Carbocyclylalkyl refers to to an acyclic akyl radical in which one of the hydrogen atoms bonded to a carbon atom is replaced with a carbocyclyl radical as described herein.
  • Typical, but non-limiting, examples of carbocyclylalkyl groups include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl .
  • Arylheteroalkyl refers to a heteroalkyl as defined herein, in which a hydrogen atom (which may be attached either to a carbon atom or a heteroatom) has been replaced with an aryl group as defined herein.
  • the aryl groups may be bonded to a carbon atom of the heteroalkyl group, or to a heteroatom of the heteroalkyl group, provided that the resulting arylheteroalkyl group provides a chemically stable moiety.
  • an arylheteroalkyl group can have the general formulae -alkylene-O-aryl, -alkylene-O-alkylene-aryl, -alkylene-NH-aryl, -alkylene-NH-alkylene-aryl, -alkylene- S-aryl, -alkylene-S-alkylene-aryl, etc.
  • any of the alkylene moieties in the general formulae above can be further substituted with any of the substituents defined or exemplified herein.
  • Heteroarylalkyl refers to an alkyl group, as defined herein, in which a hydrogen atom has been replaced with a heteroaryl group as defined herein.
  • Non- limiting examples of heteroaryl alkyl include -CH 2 -pyridinyl, -CH 2 -pyrrolyl,
  • optionally substituted in reference to a particular moiety of the compound of Formula I-II (e.g., an optionally substituted aryl group) refers to a moiety wherein all substiutents are hydrogen or wherein one or more of the hydrogens of the moiety may be replaced by substituents such as those listed under the definition of "substituted”.
  • the term "optionally replaced” in reference to a particular moiety of the compound of Formula I-II e.g., the carbon atoms of said (Ci-Cg)alkyl may be optionally replaced by -0-, -S-, or -NR a -) means that one or more of the methylene groups of the (Ci-C8)alkyl may be replaced by 0, 1 , 2, or more of the groups specified (e.g., -0-, -S-, or -NR a -).
  • non-terminal carbon atom(s) in reference to an alkyl, alkenyl, alkynyl, alkylene, alkenylene, or alkynylene moiety refers to the carbon atoms in the Attorney Docket No. 843. PF moiety that intervene between the first carbon atom of the moiety and the last carbon atom in the moiety. Therefore, by way of example and not limitation, in the alkyl moiety -CH 2 (C * )H 2 (C * )H 2 CH 3 or alkylene moiety -CH 2 (C * )H 2 (C * )H 2 CH 2 - the C * atoms would be considered to be the non-terminal carbon atoms.
  • Certain Y and Y 1 alternatives are nitrogen oxides such as + N(0)(R) or
  • Linker or “link” means a chemical moiety comprising a covalent bond or a chain of atoms.
  • Linkers include repeating units of alkyloxy (e.g. polyethyleneoxy, PEG, polymethyleneoxy) and alkylamino (e.g. polyethyleneamino, JeffamineTM); and diacid ester and amides including succinate, succinamide, diglycolate, malonate, and caproamide.
  • oxygen-linked means that if a bond between two moieties can be formed by using more than one type of atom in a moiety, then the bond formed between the moieties is through the atom specified.
  • a nitrogen-linked amino acid would be bonded through a nitrogen atom of the amino acid rather than through an oxygen or carbon atom of the amino acid.
  • the carbon atoms of the compounds of Formula I-II are intended to have a valence of four.
  • the remaining carbon substitutents needed to provide a valence of four should be assumed to be hydrogen. For example, Attorney Docket No. 843.PF
  • Protecting group refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole.
  • the chemical substructure of a protecting group varies widely.
  • One function of a protecting group is to serve as an intermediate in the synthesis of the parental drug substance.
  • Protected compounds may also exhibit altered, and in some cases, optimized properties in vitro and in vivo, such as passage through cellular membranes and resistance to enzymatic degradation or sequestration. In this role, protected compounds with intended therapeutic effects may be referred to as prodrugs.
  • Another function of a protecting group is to convert the parental drug into a prodrug, whereby the parental drag is released upon conversion of the prodrug in vivo. Because active prodrugs may be absorbed more effectively than the parental drug, prodrugs may possess greater potency in vivo than the parental drag.
  • Protecting groups are removed either in vitro, in the instance of chemical intermediates, or in vivo, in the case of prodrugs. With chemical intermediates, it is not particularly important that the resulting products after deprotection, e.g. alcohols, be physiologically acceptable, although in general it is more desirable if the products are pharmacologically innocuous.
  • Prodrug moiety means a labile functional group which separates from the active inhibitory compound during metabolism, systemically, inside a cell, by hydrolysis, enzymatic cleavage, or by some other process (Bundgaard, Hans, "Design and
  • Enzymes which are capable of an enzymatic activation mechanism with the phosphonate prodrug compounds of the invention include, but are not limited to, amidases, esterases, microbial enzymes, phospholipases, cholinesterases, and
  • Prodrug moieties can serve to enhance solubility, absorption and
  • a prodrug moiety may include an active metabolite or drug itself.
  • acyloxyalkyl ester was used as a prodrug strategy for carboxylic acids and then applied to phosphates and phosphonates by Farquhar et al Attorney Docket No. 843.PF (1983) J. Pharm. Sci. 72: 324; also US Patent Nos. 4816570, 4968788, 5663159 and 5792756.
  • a prodrug moiety is part of a phosphate group.
  • the acyloxyalkyl ester may be used to deliver phosphoric acids across cell membranes and to enhance oral bioavailability.
  • a close variant of the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester (carbonate), may also enhance oral bioavailability as a prodrug moiety in the compounds of the combinations of the invention.
  • An exemplary acyloxymethyl ester is pivaloyloxymethoxy, (POM)
  • the phosphate group may be a phosphate prodrug moiety.
  • the prodrug moiety may be sensitive to hydrolysis, such as, but not limited to those comprising a
  • the prodrug moiety may be sensitive to enzymatic potentiated cleavage, such as a lactate ester or a phosphonamidate-ester group.
  • Aryl esters of phosphorus groups are reported to enhance oral bioavailability (DeLambert et al (1994) J. Med. Chem. 37: 498). Phenyl esters containing a carboxylic ester ortho to the phosphate have also been described (Khamnei and Torrence, (1996) J. Med. Chem. 39:4109-4115). Benzyl esters are reported to generate the parent phosphonic acid. In some cases, substituents at the ortho-ox T ⁇ ara-position may accelerate the hydrolysis. Benzyl analogs with an acylated phenol or an alkylated phenol may generate the phenolic compound through the action of enzymes, e.g. esterases, oxidases, etc., which in turn undergoes cleavage at the benzylic C-0 bond to generate the phosphoric acid and the quinone methide
  • prodrugs examples include Mitchell et al (1992) J. Chem. Soc. Perkin Trans. 72345; Brook et al WO 91/19721. Still other benzylic prodrugs have been described containing a carboxylic ester-containing group attached to the benzylic methylene (Glazier et al WO 91/19721). Thio-containing prodrugs are reported to be useful for the intracellular delivery of phosphonate drugs. These proesters contain an ethylthio group in which the thiol group is either esterified with an Attorney Docket No. 843.PF acyl group or combined with another thiol group to form a disulfide.
  • a compound of Formula I-II and its pharmaceutically acceptable salts may exist as different polymorphs or pseudopolymorphs. As used herein, crystalline
  • polymorphism means the ability of a crystalline compound to exist in different crystal structures.
  • the crystalline polymorphism may result from differences in crystal packing (packing polymorphism) or differences in packing between different
  • crystalline pseudopolymorphism means the ability of a hydrate or solvate of a
  • the pseudopolymorphs of the instant invention may exist due to differences in crystal packing (packing)
  • the instant invention comprises all polymorphs and pseudopolymorphs of the compounds of Formula I-II and their pharmaceutically acceptable salts.
  • a compound of Formula I-II and its pharmaceutically acceptable salts may also exist as an amorphous solid.
  • an amorphous solid is a solid in which there is no long-range order of the positions of the atoms in the solid. This definition applies as well when the crystal size is two nanometers or less.
  • Additives, including solvents, may be used to create the amorphous forms of the instant invention.
  • the Attorney Docket No. 843.PF instant invention comprises all amorphous forms of the compounds of Formula I-II and their pharmaceutically acceptable salts.
  • R x comprises a R y substituent.
  • R y can be R.
  • R can be W 3 .
  • W 3 can be W 4 and W 4 can be R or comprise substituents comprising R y .
  • One of ordinary skill in the art of medicinal chemistry understands that the total number of such substituents is reasonably limited by the desired properties of the compound intended.
  • properties include, by way of example and not limitation, physical properties such as molecular weight, solubility or log P, application properties such as activity against the intended target, and practical properties such as ease of synthesis.
  • W 3 and R y are recursive substituents in certain embodiments.
  • each recursive substituent can independently occur 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0, times in a given embodiment.
  • each recursive substituent can independently occur 12 or fewer times in a given embodiment.
  • each recursive substituent can independently occur 3 or fewer times in a given embodiment.
  • W 3 will occur 0 to 8 times
  • R y will occur 0 to 6 times in a given embodiment.
  • W 3 will occur 0 to 6 times and R y will occur 0 to 4 times in a given
  • Recursive substituents are an intended aspect of the invention.
  • One of ordinary skill in the art of medicinal chemistry understands the versatility of such substituents.
  • the modifier "about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (e.g., includes the degree of error associated with measurement of the particular quantity).
  • Attorney Docket No. 843.PF The compounds of the Formula I-II may comprise a phosphate group as R 7 ,
  • W 1 and W 2 when taken together, are -Y 3 (C(R y ) 2 ) 3 Y 3 -; or one of W 1 or W 2 together with either R 3 or R 4 is -Y 3 - and the other of W 1 or W 2 is Formula la; or W 1 and W 2 are each, independently, a group of Formula la:
  • each Y 2 is independently a bond, O, CR 2 , NR, + N(0)(R), N(OR), + N(0)(OR), N-NR 2 , S, S-S, S(O), or S(0) 2 ;
  • each R x is independently R y , a protecting group, or the formula: Attorney Docket No. 843. PF
  • Mia, Ml c, and Mid are independently 0 or 1 ;
  • M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • each R is H, halogen, (Ci-Cg) alkyl, (Ci-C 8 ) substituted alkyl, (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) substituted alkenyl, (C 2 -C 8 ) alkynyl, (C 2 -C ) substituted alkynyl, C 6 -C 2 o aryl, C 6 -C 2 o substituted aryl, C 2 -C 20 heterocycle, C 2 -C 20 substituted heterocyclyl, arylalkyl, substituted arylalkyl or a protecting group;
  • W 3 is W 4 or W 5 ;
  • W 4 is R, -C(Y 1 )R y , -C(Y ! )W 5 , -S0 2 R y , or -S0 2 W 5 ; and
  • W 5 is a carbocycle or a heterocycle wherein W 5 is independently substituted with 0 to 3 R y groups.
  • a W 5 heterocycle may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S).
  • W 5 heterocyclic monocycles may have 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S); or 5 or 6 ring atoms (3 to 5 carbon atoms and 1 to 2 heteroatoms selected from N and S).
  • W 5 heterocyclic bicycles have 7 to 10 ring atoms (6 to 9 carbon atoms and 1 to 2 heteroatoms selected from N, O, and Attorney Docket No.
  • PF S arranged as a bicyclo [4,5], [5,5], [5,6], or [6,6] system; or 9 to 10 ring atoms (8 to 9 carbon atoms and 1 to 2 hetero atoms selected from N and S) arranged as a bicyclo
  • the W heterocycle may be bonded to Y through a carbon, nitrogen, sulfur or other atom by a stable covalent bond.
  • substituted phenyl carbocycles include: Attorney Docket No. 843.PF
  • substructures such as:
  • each Y is, independently, O or N(R).
  • each Y is O and each R x is inde endently:
  • Ml 2c is 1 , 2 or 3 and each Y 2 is independently a bond, O, CR 2 , or S.
  • one Y 2b -R is NH(R) and the other Y 2b -R x is 0-R x wherein R is:
  • each Y is O and each R x is inde endently:
  • Another embodiment of of Formula I-II includes the
  • each Y c is, independently, O, N(R y ) or S.
  • Another embodiment of of Formula I-II compounds includes the substructures wherein one of W or W together with either R is -Y - and the other of W or W is Formula la.
  • Such an embodiment is represented by a compound of Formula lb selected from:
  • Ml 2c is 1, 2 or 3 and each Y is independently a bond, O, CR 2 , or S.
  • W 1 or W 2 is Y 2b -R x ; each Y, Y 3 and Y 2b is O and R x is: Attorney Docket No. 843.PF
  • Another embodiment of of Formula I-II compounds includes a substructure:
  • W is a carbocycle such as phenyl or substituted phenyl.
  • the substructure is: Attorney Docket No. 843. PF
  • R x is:
  • Ml 2c is 1, 2 or 3 and each Y 2 is independently a bond, O, CR 2 , or S.
  • R y is (Ci-C 8 ) alkyl, (Ci-Cg) substituted alkyl, (C 2 - Cg) alkenyl, (C 2 -Cg) substituted alkenyl, (C 2 -C 8 ) alkynyl or (C 2: C 8 ) substituted alkynyl;
  • R is CH 3 ; and each Y 2 is -NH-.
  • W 1 and W2 are, independently, nitrogen-linked, naturally occurring amino acids or naturally occurring amino acid esters.
  • W 1 and W 2 are,
  • each R is, independently, (Ci-C 8 ) alkyl.
  • each R x is, independently, C6-C 2 o aryl or C 6 -C 2 o substituted aryl.
  • each R 2! is independently H or (C 1 -C 8 )alkyl
  • each R is independently H, R , R or R wherein each R is independently substituted with 0 to 3 R 23 ;
  • each R 23a is independently F, CI, Br, I, -CN, N 3 or -N0 2 ;
  • each R 24 is independently (Ci-Cg)alkyl, (C 2 -C 8 )alkenyl, or (C 2 -C8)alkynyl;
  • each R 25a is independently (Ci-Cg)alkylene, (C 2 -C 8 )alkenylene, or (C 2 -
  • C 8 )alkynylene is substituted with 0-3 R groups
  • each Y is independently O or S.
  • Embodiments of R x include esters, carbamates, carbonates, thioesters, amides, thioamides and urea groups:
  • Any reference to the compounds of the invention described heerein also includes a reference to a physiologically acceptable salt thereof.
  • physiologically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkali metal or an alkaline earth (for example,
  • Physiologically acceptable salts of a nitrogen atom or an amino group include (a) acid addition salts formed with inorganic acids, for example, hydrochloric acid,
  • hydrobromic acid sulfuric acid, sulfamic acids, phosphoric acid, nitric acid and the like; (b) salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, Attorney Docket No. 843. PF p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid,
  • compound of a hydroxy group include the anion of said compound in combination with a suitable cation such as Na + and NR 4 + .
  • compositions herein comprise compounds of the invention in their un-ionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.
  • racemic and diastereomeric mixtures are separated into their individual, substantially optically pure isomers through well-known techniques such as, for example, the separation of diastereomeric salts formed with optically active adjuncts, e.g., acids or bases followed by conversion back to the Attorney Docket No. 843.PF optically active substances.
  • optically active adjuncts e.g., acids or bases followed by conversion back to the Attorney Docket No. 843.PF optically active substances.
  • the desired optical isomer is synthesized by means of stereospecific reactions, beginning with the appropriate stereoisomer of the desired starting material.
  • chiral refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
  • stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
  • Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography.
  • Enantiomers refer to two stereoisomers of a compound which are non- superimposable mirror images of one another.
  • dextrorotatory For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another.
  • a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomer
  • racemic mixture A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or Attorney Docket No. 843. PF stereospecificity in a chemical reaction or process.
  • racemic mixture and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
  • Another aspect of the invention relates to methods of inhibiting the activity of Orthomyxoviridae polymerase comprising the step of treating a sample suspected of containing Orthomyxoviridae virus with a composition of the invention.
  • compositions of the invention may act as inhibitors of Orthomyxoviridae polymerase , as intermediates for such inhibitors or have other utilities as described below.
  • the inhibitors will bind to locations on the surface or in a cavity of
  • substantially irreversibly binding compositions are useful as probes for the detection of Orthomyxoviridae polymerase. Accordingly, the invention relates to methods of detecting Orthomyxoviridae polymerase in a sample suspected of containing
  • Orthomyxoviridae polymerase comprising the steps of: treating a sample suspected of containing Orthomyxoviridae polymerase with a composition comprising a compound Attorney Docket No. 843.PF of the invention bound to a label; and observing the effect of the sample on the activity of the label.
  • Suitable labels are well known in the diagnostics field and include stable free radicals, fluorophores, radioisotopes, enzymes, chemiluminescent groups and chromogens.
  • the compounds herein are labeled in conventional fashion using functional groups such as hydroxyl, carboxyl, sulfhydryl or amino.
  • the treating step of the invention comprises adding the composition of the invention to the sample or it comprises adding a precursor of the composition to the sample.
  • the addition step comprises any method of administration as described herein.
  • the activity of Orthomyxoviridae polymerase after application of the composition can be observed by any method including direct and indirect methods of detecting Orthomyxoviridae polymerase activity. Quantitative, qualitative, and semiquantitative methods of determining Orthomyxoviridae polymerase activity are all contemplated. Typically one of the screening methods described above are applied, however, any other method such as observation of the physiological properties of a living organism are also applicable.
  • Organisms that contain Orthomyxoviridae polymerase include the following:
  • the present application provides for methods of inhibiting Orthomyxoviridae polymerase in a cell, comprising: contacting a cell infected with Orthomyxoviridae virus with an effective amount of a compound of Formula I-II, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, and at least one additional active therapeutic agent, whereby the Orthomyxoviridae
  • M2 ion channel blockers Orthomyxoviridae RNA-dependent RNA
  • the compounds of this invention are formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice.
  • Tablets will contain excipients, glidants, fillers, binders and the like.
  • Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. All formulations will optionally contain excipients such as those set forth in the "Handbook of Pharmaceutical Excipients" (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and Attorney Docket No. 843.PF the like.
  • the pH of the formulations ranges from about 3 to about 11, but is ordinarily about 7 to 10.
  • the formulations both for veterinary and for human use, of the invention comprise at least one active ingredient, as above defined, together with one or more acceptable carriers therefor and optionally other therapeutic ingredients.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.
  • the formulations include those suitable for the foregoing administration routes.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack),
  • Such methods include the step of bringing into
  • the active ingredient with the carrier which constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be administered as a bolus, electuary or paste.
  • a tablet is made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid Attorney Docket No. 843 ,PF diluent.
  • the tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom.
  • the active ingredients may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof.
  • a polyhydric alcohol i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof.
  • formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas.
  • dermal penetration enhancers include dimethyl sulphoxide and related analogs.
  • emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • Emulgents and emulsion stabilizers suitable for use in the formulation of the invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate. Attorney Docket No. 843.PF
  • the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties.
  • the cream should preferably be a non-greasy, non- staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di- isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils are used.
  • compositions according to the present invention comprise a combination according to the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents.
  • compositions containing the active ingredient may be in any form suitable for the intended method of administration.
  • tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
  • Tablets containing the active ingredient in admixture with non-toxic pharmaceutically may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically
  • excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a Attorney Docket No. 843. PF sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium
  • phosphate or kaolin or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • oil medium such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally-occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate).
  • the aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
  • Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
  • Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives.
  • a dispersing or wetting agent and suspending agents are exemplified by those Attorney Docket No. 843. PF disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these.
  • Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally-occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as
  • compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder.
  • a non-toxic parenterally acceptable diluent or solvent such as a solution in 1,3-butane-diol or prepared as a lyophilized powder.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid may likewise be used in the preparation of injectables.
  • a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material Attorney Docket No. 843.PF which may vary from about 5 to about 95% of the total compositions (weigh weight).
  • the pharmaceutical composition can be prepared to provide easily measurable amounts for administration.
  • an aqueous solution intended for intravenous infusion may contain from about 3 to 500 ⁇ g of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
  • a suitable carrier especially an aqueous solvent for the active ingredient.
  • the active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%,
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns, such as 0.5, 1, 30, 35 etc., which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs.
  • Suitable formulations include aqueous or oily solutions of the active ingredient.
  • Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis of Orthomyxoviridae infections as described below.
  • the invention is a novel, efficacious, safe, nonirritating and physiologically compatible inhalable composition
  • a compound of Formula I-II or a pharmaceutically acceptable salt thereof, suitable for treating
  • the inhalable formulation is delivered to the endobronchial space in an aerosol comprising particles with a mass median aerodynamic diameter (MMAD) between about 1 and about 5 ⁇ .
  • MMAD mass median aerodynamic diameter
  • the compound of Formula I-II is formulated for aerosol delivery using a nebulizer, pressurized metered dose inhaler (pMDI), or dry powder inhaler (DPI).
  • Non-limiting examples of nebulizers include atomizing, jet, ultrasonic, pressurized, vibrating porous plate, or equivalent nebulizers including those nebulizers utilizing adaptive aerosol delivery technology (Denyer, J. Aerosol medicine Pulmonaiy Drug Delivery 2010, 23 Supp 1, S1-S10).
  • a jet nebulizer utilizes air pressure to break a liquid solution into aerosol droplets.
  • An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets.
  • a pressurized nebulization system forces solution under pressure through small pores to generate aerosol droplets.
  • a vibrating porous plate device utilizes rapid vibration to shear a stream of liquid into appropriate droplet sizes.
  • the formulation for nebulization is delivered to the endobronchial space in an aerosol comprising particles with a MMAD predominantly between about 1 ⁇ and about 5 ⁇ using a nebulizer able to aerosolize the
  • the majority of aerosolized particles should not have a MMAD greater than about 5 ⁇ . If an aerosol contains a large number of particles with a MMAD larger than 5 ⁇ , the particles are deposited in the upper airways decreasing the amount of drug delivered to the site of inflammation and bronchoconstriction in the lower respiratory tract. If the MMAD of the aerosol is smaller than about 1 ⁇ , then the particles have a tendency to remain suspended in the inhaled air and are subsequently exhaled during expiration.
  • the aerosol formulation for nebulization delivers a therapeutically efficacious dose of the Attorney Docket No. 843.PF compound of Formula I-II to the site of Orthomyxoviridae infection sufficient to treat the Orthomyxoviridae infection.
  • the amount of drug administered must be adjusted to reflect the efficiency of the delivery of a therapeutically efficacious dose of the compound of Formula I-II.
  • a combination of the aqueous aerosol formulation with the atomizing, jet, pressurized, vibrating porous plate, or ultrasonic nebulizer permits, depending on the nebulizer, about, at least, 20, to about 90%, typically about 70% delivery of the administered dose of the compound of
  • Formula I-II into the airways In a preferred embodiment, at least about 30 to about 50% of the active compound is delivered. More preferably, about 70 to about 90% of the active compound is delivered.
  • a compound of Formula I-II or a pharmaceutically acceptable salt thereof is delivered as a dry inhalable powder.
  • the compounds of the invention are administered endobronchially as a dry powder formulation to efficacious deliver fine particles of compound into the endobronchial space using dry powder or metered dose inhalers.
  • the compound of Formula I-II is processed into particles with, predominantly, MMAD between about 1 ⁇ and about 5 ⁇ by milling spray drying, critical fluid processing, or precipitation from solution. Media milling, jet milling and spray-drying devices and procedures capable of producing the particle sizes with a MMAD between about 1 ⁇ and about 5 ⁇ are well know in the art.
  • excipients are added to the
  • excipients are blended with the particles of the required size to aid in dispersion of the drug particles, for example by using lactose as an excipient.
  • Particle size determinations are made using devices well known in the art.
  • a multi-stage Anderson cascade impactor or other suitable method such as those specifically cited within the US Pharmacopoeia Chapter 601 as characterizing devices for aerosols within metered-dose and dry powder inhalers.
  • a compound of Formula I-II is delivered as a dry powder using a device such as a dry powder inhaler or other dry powder dispersion Attorney Docket No. 843.PF devices.
  • a device such as a dry powder inhaler or other dry powder dispersion Attorney Docket No. 843.PF devices.
  • dry powder inhalers and devices include those disclosed in US5,458,135; US5,740,794; US5775320; US5,785,049; US3,906,950;
  • MMAD small particles of MMAD from 1 ⁇ and about 5 ⁇ , and often involve co- formulation with larger excipient particles such as, but not limited to, lactose.
  • Drug powder is placed in the inhalation chamber (either by device metering or by breakage of a factory-metered dosage) and the inspiratory flow of the patient accelerates the powder out of the device and into the oral cavity.
  • Non-laminar flow characteristics of the powder path cause the excipient-drug aggregates to decompose, and the mass of the large excipient particles causes their impaction at the back of the throat, while the smaller drug particles are deposited deep in the lungs.
  • a compound of Formula I-II, or a pharmaceutically acceptable salt thereof is delivered as a dry powder using either type of dry powder inhaler as described herein, wherein the MMAD of the dry powder, exclusive of any excipients, is predominantly in the range of 1 ⁇ to about 5 ⁇ .
  • a compound of Formula I-II is delivered as a dry powder using a metered dose inhaler.
  • metered dose inhalers and devices include those disclosed in US5,261,538; US5, 544,647;
  • a compound of Formula I-II, or a pharmaceutically acceptable salt thereof is delivered as a dry powder using a metered dose inhaler wherein the MMAD of the dry powder, exclusive of any excipients, is predominantly in the range of about 1-5 ⁇ .
  • Formulations suitable for vaginal administration may be presented as pessaries, Attorney Docket No. 843.PF tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous and nonaqueous sterile injection solutions which may contain anti-oxidants, buffers,
  • bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient
  • aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • formulations are presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use.
  • sterile liquid carrier for example water for injection
  • suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.
  • formulations of this invention may include other agents
  • those suitable for oral administration may include flavoring agents.
  • the invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefor.
  • Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.
  • controlled release formulations pharmaceutical formulations containing as active ingredient one or more compounds of the invention in which the release of the active ingredient are controlled and regulated to allow less frequency dosing or to improve the Attorney Docket No. 843. PF pharmacokinetic or toxicity profile of a given active ingredient.
  • the effective dose of active ingredient depends, at least, on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower doses) or against an active viral infection, the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies. It can be expected to be from about 0.0001 to about 100 mg/kg body weight per day; typically, from about 0.01 to about 10 mg/kg body weight per day; more typically, from about .01 to about 5 mg/kg body weight per day; most typically, from about .05 to about 0.5 mg/kg body weight per day.
  • the daily candidate dose for an adult human of approximately 70 kg body weight will range from 1 mg to 1000 mg, preferably between 5 mg and 500 mg, and may take the form of single or multiple doses.
  • One or more compounds of the invention are administered by any route appropriate to the condition to be treated.
  • Suitable routes include oral, inhalation, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular,
  • intravenous, intradermal, intrathecal and epidural intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with for example the condition of the recipient.
  • the present application discloses pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, in combination with at least one additional therapeutic agent, and a pharmaceutically acceptable carrier or exipient.
  • Attorney Docket No. 843.PF For the treatment of Orthomyxoviridae virus infections, preferably, the other active therapeutic agent is active against Orthomyxoviridae virus infections,
  • Non-limiting examples of these other active therapeutic agents are viral haemagglutinin inhibitors, viral neuramidase inhibitors, M2 ion channel blockers, Orthomyxoviridae RNA-dependent RNA polymerases inhibitors and sialidases.
  • Non-limiting examples of neuramidase inhibitors include oseltamivir, zanamivir, laninamivir, peramivir and CS-8958.
  • Non-limiting examples of viral M2 channel inhibitors include amantadine and rimantadine.
  • Non-limiting examples of Orthomyxoviridae RNA-dependent RNA polymerases inhibitors are ribavirin and favipiravir.
  • Non-limiting examples of sialidases are DAS181.
  • Orthomyxoviridae viruses are respiratory infections. Therefore, additional active therapeutics used to treat respiratory symptoms and sequelae of infection may be used in combination with the compounds of Formula I-II.
  • additional therapeutic agents in combination with the compounds of Formula I-II for the treatment of viral respiratory infections include, but are not limited to, bronchodilators and corticosteroids.
  • Glucocorticoids which were first introduced as an asthma therapy in 1950 (Carryer, Journal of Allergy, 21, 282-287, 1950), remain the most potent and
  • glucocorticoid therapies are associated with profound undesirable side effects such as truncal obesity, hypertension, glaucoma, glucose intolerance, acceleration of cataract formation, bone mineral loss, and psychological effects, all of which limit their use as long-term therapeutic agents (Goodman and Gilman, 10th edition, 2001).
  • a solution to systemic side effects is to deliver steroid drugs directly to the site of inflammation.
  • Inhaled corticosteroids (ICS) have been developed to mitigate the severe adverse effects of oral steroids.
  • ICS Inhaled corticosteroids
  • dexamethasone dexamethasone sodium phosphate, fluorometholone, fluorometholone acetate, loteprednol, loteprednol etabonate, hydrocortisone, prednisolone, Attorney Docket No. 843.PF fludrocortisones, triamcinolone, triamcinolone acetonide, betamethasone,
  • anti-inflammatory signal transduction modulators like phosphodiesterase inhibitors (e.g. PDE-4, PDE-5, or PDE-7 specific), transcription factor inhibitors (e.g. blocking NFKB through IKK inhibition), or kinase inhibitors (e.g.
  • non-limiting additional therapeutic agents include: 5-(2,4-Difluoro-phenoxy)-l-isobutyl-lH- indazole-6-carboxylic acid (2 -dimethyl amino-ethyl)-amide (P38 Map kinase inhibitor ARPvY-797); 3-Cyclopropylmethoxy-N-(3,5-dichloro-pyridin-4-yl)-4- difluorormethoxy-benzamide (PDE-4 inhibitor Roflumilast); 4-[2-(3-cyclopentyloxy-4- methoxyphenyl)-2-phenyl-ethyl]-pyridine (PDE-4 inhibitor CDP-840); N-(3,5- dichloro-4-pyridinyl)-4-(difluoromethoxy)-8-[(methylsulfonyl)amino]-l- dibenzofurancarboxamide (PDE-4 inhibitor Oglemilast); N-(3,5-Dichloro-pyr
  • Combinations comprising inhaled p2-adrenoreceptor agonist bronchodilators such as formoterol, albuterol or salmeterol with the compounds of Formula I-II are also suitable, but non-limiting, combinations useful for the treatment of respiratory viral infections.
  • Combinations of inhaled p2-adrenoreceptor agonist bronchodilators such as formoterol or salmeterol with ICS's are also used to treat both the bronchoconstriction and the inflammation (Symbicort® and Advair®, respectively).
  • the combinations comprising these ICS and p2-adrenoreceptor agonist combinations along with the compounds of Formula I-II are also suitable, but non-limiting, combinations useful for the treatment of respiratory viral infections.
  • anticholinergics are of potential use and, therefore, useful as an additional therapeutic agents in combination with the compounds of Formula I-II for the treatment of viral respiratory infections.
  • anticholinergics include, but are not limited to,
  • the compounds of Formula I-II may also be combined with mucolytic agents to treat both the infection and symptoms of respiratory infections.
  • a non-limiting example of a mucolytic agent is ambroxol.
  • the compounds of Formula I-II may be combined with expectorants to treat both the infection and symptoms of respiratory infections.
  • a non-limiting example of an expectorant is guaifenesin.
  • Nebulized hypertonic saline is used to improve immediate and lon-term clearance of small airways in patients with lung diseases (Kuzik, J. Pediatrics 2007, 266).
  • the compounds of Formula I-II may also be combined with nebulized
  • the combination of the compounds of Formula I-II with hypertonic saline may also comprise any of the additional agents discussed above.
  • nebulized about 3% hypertonic saline is used.
  • any compound of the invention with one or more other active therapeutic agents in a unitary dosage form for simultaneous or sequential administration to a patient.
  • the combination therapy may be administered as a simultaneous or sequential regimen.
  • the combination When administered sequentially, the combination may be administered in two or more administrations.
  • Co-administration of a compound of the invention with one or more other active therapeutic agents generally refers to simultaneous or sequential administration of a compound of the invention and one or more other active therapeutic agents, such that Attorney Docket No. 843. PF therapeutically effective amounts of the compound of the invention and one or more other active therapeutic agents are both present in the body of the patient.
  • Co-administration includes administration of unit dosages of the compounds of the invention before or after administration of unit dosages of one or more other active therapeutic agents, for example, administration of the compounds of the invention within seconds, minutes, or hours of the administration of one or more other active therapeutic agents.
  • a unit dose of a compound of the invention can be administered first, followed within seconds or minutes by administration of a unit dose of one or more other active therapeutic agents.
  • a unit dose of one or more other therapeutic agents can be administered first, followed by administration of a unit dose of a compound of the invention within seconds or minutes.
  • a unit dose of a compound of the invention may be desirable to administer a unit dose of a compound of the invention first, followed, after a period of hours (e.g., 1 -12 hours), by administration of a unit dose of one or more other active therapeutic agents.
  • a period of hours e.g. 1-12 hours
  • the combination therapy may provide "synergy” and "synergistic", i.e. the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately.
  • a synergistic effect may be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen.
  • a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g. in separate tablets, pills or capsules, or by different injections in separate syringes.
  • an effective dosage of each active ingredient is administered sequentially, i.e. serially
  • effective dosages of two or more active ingredients are
  • a synergistic anti-viral effect denotes an antiviral effect which Attorney Docket No. 843.PF is greater than the predicted purely additive effects of the individual compounds of the combination.
  • the present application provides for methods of treating Orthomyxoviridae infections in a patient, comprising: administering to the patient a therapeutically effective amount of a compound of Formula I-II, or a pharmaceutically acceptable salt, solvate, and/or ester thereof.
  • the present application provides for methods of treating Orthomyxoviridae infections in a patient, comprising: administering to the patient a therapeutically effective amount of a compound of Formula I-II, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, and at least one additional active therapeutic agent, whereby Orthomyxoviridae polymerase is inhibited.
  • the present application provides for methods of treating Orthomyxoviridae infections in a patient, comprising: administering to the patient a therapeutically effective amount of a compound of Formula I-II, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, and at least one additional active therapeutic agent selected from the group consisting of interferons, ribavirin analogs, a viral haemagglutinin inhibitor, a viral neuramidase inhibitor, a M2 ion channel blocker, a Orthomyxoviridae RNA-dependent RNA polymerase inhibitor, a sialidase and other drugs for treating Orthomyxoviridae infections.
  • the present application provides for the use of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, for the preparation of a medicament for treating an
  • Orthomyxoviridae infections in a patient Orthomyxoviridae infections in a patient.
  • the invention includes novel and unobvious compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof.
  • a radiolabelled (e.g. or 3 ⁇ 4) compound of the invention typically are identified by preparing a radiolabelled (e.g. or 3 ⁇ 4) compound of the invention, administering it parenterally in a detectable dose (e.g. greater than about 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur
  • the metabolite structures are determined in conventional fashion, e.g. by MS or NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well-known to those skilled in the art.
  • the conversion products so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention even if they possess no Orthomyxoviridae polymerase inhibitory activity of their own.
  • compositions and methods for determining stability of compounds in surrogate gastrointestinal secretions are known.
  • Compounds are defined herein as stable in the gastrointestinal tract where less than about 50 mole percent of the protected groups are deprotected in surrogate intestinal or gastric juice upon incubation for 1 hour at 37°C. Simply because the compounds are stable to the gastrointestinal tract does not mean that they cannot be hydrolyzed in vivo.
  • the prodrugs of the invention typically will be stable in the digestive system but may be substantially hydrolyzed to the parental drug in the digestive lumen, liver or other metabolic organ, or within cells in general.
  • n-BuLi 7.5 mL of a 1.6 M solution in hexanes, 12.0 mmol
  • the benzylated nucleoside material (0.134 g, 0.290 mmol), Degussa catalyst (0.268 g) and AcOH (30 mL) were mixed together.
  • the reaction atmosphere was charged with H 2 (g) and the reaction stirred for 2 h.
  • the catalyst was removed by Attorney Docket No. 843. PF filtration and the mixture concentrated under reduced pressure. The residue was dissolved in a minimal amount of H 2 0 and subjected to reverse phase HPLC (C 18 hydro P column) to isolate the ⁇ -anomer (8 ⁇ ) (0.086 g, 0.217 mmol, 57% yield).
  • the nucleoside 8 ⁇ (0.022 g, 0.056 mmol) was dissolved in trimethylphosphate (1 mL) and stirred under N 2 (g). Phosphorous oxychloride (0.067 mL, 0.73 mmol) was added and the mixture stirred for 2 h. Monitoring by analytical ion-exchange column determined the time at which > 80 percent of monophosphate was formed. A solution of tributylamine (0.44 mL, 1.85 mmol) and triethylammonium pyrophosphate (0.327 g, Attorney Docket No. 843.PF 0.72 mmol) dissolved in anhydrous DMF (1 mL) was added. The reaction mixture was stirred for 20 min and then quenched by the addition of IN triethylammonium
  • nucleoside 1 21 mg, 0.078 mmol
  • trimethyl phosphate 1.0 mL
  • POCl 3 58 mg, 0.378 mmol
  • the reaction was stirred at 0 °C for 2 h after which, a small aliquot was removed and hydrolyzed with 1.0 M triethylammonium bicarbonate buffer and analyzed by ion exchange HPLC to ensure generation of the nucleoside dichlorophosphoridate.
  • the solid was dissolved in water (5.0 mL) and purified by ion exchange HPLC. Fractions containing the desired product were pooled and lyophilized to give the desired triphosphate (35 mg) as a colorless solid. Analysis by P NMR indicated that the material was not of sufficient purity.
  • the solid was dissolved in water (5.0 mL) and stirred with solid NaHC0 3 (50 mg) for 15 min. The water was removed under reduced pressure and the residue was co-evaporated from water (x4) to give a solid that was purified by reverse phase HPLC. Fractions containing the desired product were pooled and evaporated to dryness to provide the desired product 11 (3.5 mg, 7%) as a colorless solid.
  • Ethyl alanine ester hydrochloride salt (1.69 g, 11 mmol) was dissolved in anhydrous CH 2 C1 2 (10 mL) and the mixture stirred with cooling to 0 °C under N 2 (g). Phenyl dichlorophosphate (1.49 mL, 10 mmol) was added followed by dropwise addition of Et 3 N over 10 min. The reaction mixture was then slowly warmed to RT and stirred for 12 h. Anhydrous Et 2 0 (50 mL) was added and the mixture stirred for 30 min. The solid that formed was removed by filtration, and the filtrate concentrated under reduced pressure. The residue was subjected to silica gel chromatography eluting with 0-50% EtOAc in hexanes to provide intermediate A (1.13 g, 39%).
  • the 2-ethylbutyl alanine chlorophosphoramidate ester B was prepared using the same procedure as chloridate A except substituting 2-ethylbutyl alanine ester for ethyl alanine ester.
  • the material is used crude in the next reaction. Treatment with methanol or ethanol forms the displaced product with the requisite LCMS signal.
  • the isopropyl alanine chlorophosphoramidate ester C was prepared using the same procedure as chloridate A except substituting isopropyl alanine ester for the ethyl alanine ester. The material is used crude in the next reaction. Treatment with methanol or ethanol forms the displaced product with the requisite LCMS signal.
  • the nucleoside (0.01 1 g, 0.04 mmol) was dissolved in trimethylphosphate (2 mL) and cooled to 0°C. The mixture was stirred under an atmosphere of N 2 (g) andl - Methylimidazole(0.320 mL, 5 mmol) followed by the alaninylmonoisopropyl, monophenol phosphorchloridate C (0.240 mL, 4.4 mmol) was added. The reaction mixture was stirred for 2 h. at 0°C and then allowed to warm slowly to RT. while monitoring by LC/MS. When complete by LCMS, the reaction mixture was treated with H 2 0 (5 mL) and then concentrated under reduced pressure.
  • the nucleoside (0.026 g, 0.092 mmol) was dissolved in trimethylphosphate (2 niL) and cooled to 0°C. The mixture was stirred under N 2 (g) and 1 -methylimidazole (0.062 mL, 0.763 mmol) followed by the chloridate A (0.160 g, 0.552 mmol) were added. The reaction mixture was stirred for 2 h. at 0°C and then allowed to warm slowly to RT. H 2 0 (5 mL) was added to quench the reaction and then the mixture concentrated under reduced pressure. The residue was dissolved in CH 2 C1 2 and subjected to silica gel chromatography eluting with 0-100% EtOAc in hexanes.
  • the product was extracted with EtOAc (100 mL x 3). The combined organic layers were dried with sodium sulfate, filtered and were concentrated. The product was purified by silica gel chromatography 90% - 30% hexanes in ethyl acetate. The product 16 was found to be a yellow solid (l .Og, 16%).
  • nucleoside 20 (7.2 mg, 0.025 mmol) in trimethyl phosphate (0.4 mL) cooled to 0 °C was added POCl 3 (25 mg, 0.151 mmol) dropwise. The reaction was stirred at 0 °C for 30 min, 2, 6-lutidine (5mg, 0.05 mmol) was added dropwise.
  • Another aspect of the invention relates to methods of inhibiting viral infections, comprising the step of treating a sample or subject suspected of needing such inhibition with a composition of the invention.
  • samples suspected of containing a virus include natural or man-made materials such as living organisms; tissue or cell cultures; biological samples such as biological material samples (blood, serum, urine,
  • cerebrospinal fluid tears, sputum, saliva, tissue samples, and the like
  • laboratory samples food, water, or air samples
  • bioproduct samples such as extracts of cells, particularly recombinant cells synthesizing a desired glycoprotein; and the like.
  • sample will be suspected of containing an organism which induces a viral infection, frequently a pathogenic organism such as a tumor virus.
  • Samples can be contained in any medium including water and organic solventYwater mixtures. Samples include living organisms such as humans, and man made materials such as cell cultures.
  • composition can be observed by any method including direct and indirect methods of detecting such activity.
  • the antiviral activity of a compound of the invention can be measured using standard screening protocols that are known.
  • the antiviral activity of a compound can be measured using the following general protocols.
  • MDCK cells were seeded in 96-well plates at a density of le5 cells per well in 100 ⁇ , of MEM culture medium with 10% FBS. Compounds were 3-fold serially diluted in complete MEM culture medium, with 100 ⁇ as the highest concentration. Each concentration was tested in duplicate. Prior to infection, cells were washed once with 200 ⁇ . serum-free MEM. Influenza A virus (A/Hong Kong/8/68, Advanced
  • cytotoxicity of the compounds in MDCK cells was determined in replicate plates in the same way as in antiviral activity assays, except no virus was added to the cell culture.
  • EC 50 and CC 50 values were calculated by nonlinear regression of multiple data sets using XLFit software (IBDS, Guildford, UK).
  • Nucleotide analog inhibitors were serially diluted 3 fold in water and added to reaction mix containing 10 % virus lysate (v/v), 100 mM Tris-HCl (pH 8.0), 100 mM KC1, 1 mM DTT, 10% glycerol, 0.25 % Triton- 101 (reduced), 5 mM MgCl 2 , 0.4 U/mL
  • NTP ribonucleotide triphosphate
  • the radiolabel used for each assay matched the class of nucleotide analog screened.
  • the concentrations for the limiting natural NTP are 20, 10, 2, and 1 ⁇ for ATP, CTP, UTP, and GTP respectively.
  • the molar ratio of un- radiolabeled: radiolabeled NTP were in the range of 100-400: 1.
  • Compound 11 had an IC 50 of 0.95-1.59 ⁇
  • Compound 9 had an IC 5 o of 2.1-2.97 ⁇
  • Compound 10 had an IC50 of 48.6-116 ⁇
  • Compound 21 had an IC 50 of 0.97-1.87 ⁇ .

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Abstract

L'invention concerne des méthodes de traitement d'infections à virus Orthomyxoviridae, par administration de ribosides, de riboside phosphates et de promédicaments de ceux-ci, de formule I, dans laquelle R2 désigne halogène. Les composés, les compositions et les méthodes de l'invention s'avèrent particulièrement utiles dans le traitement d'infections par le virus de la grippe humaine.
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Families Citing this family (60)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MY164523A (en) 2000-05-23 2017-12-29 Univ Degli Studi Cagliari Methods and compositions for treating hepatitis c virus
CA2506129C (fr) 2002-11-15 2015-02-17 Idenix (Cayman) Limited Nucleoside a ramification en 2' et mutation de flaviviridae
ES2398684T3 (es) 2008-04-23 2013-03-21 Gilead Sciences, Inc. Análogos de carbanucleósido para el tratamiento antiviral
MX2012003126A (es) 2009-09-21 2012-06-19 Gilead Sciences Inc Procesos e intermedios para la preparacion de analogos de 1'-carbonucleosidos sustituidos.
BR112013001267A2 (pt) 2010-07-19 2016-05-17 Gilead Sciences Inc métodos para a preparação de pró-fármacos de fosforamidato diasteromericamente puro
US20120027752A1 (en) 2010-07-22 2012-02-02 Gilead Sciences, Inc. Methods and compounds for treating paramyxoviridae virus infections
EP2691409B1 (fr) 2011-03-31 2018-02-21 Idenix Pharmaceuticals LLC. Composés et compositions pharmaceutiques pour le traitement d'infections virales
US9403863B2 (en) 2011-09-12 2016-08-02 Idenix Pharmaceuticals Llc Substituted carbonyloxymethylphosphoramidate compounds and pharmaceutical compositions for the treatment of viral infections
JP6242378B2 (ja) * 2012-03-13 2017-12-06 ギリアード サイエンシーズ， インコーポレイテッド 抗ウイルス処置のための２’−置換カルバヌクレオシド類似体
AU2013266393B2 (en) 2012-05-22 2017-09-28 Idenix Pharmaceuticals Llc D-amino acid compounds for liver disease
WO2013177195A1 (fr) 2012-05-22 2013-11-28 Idenix Pharmaceuticals, Inc. Promédicaments de 3',5'-phosphate cyclique pour traiter une infection par le virus de l'hépatite c
US9109001B2 (en) 2012-05-22 2015-08-18 Idenix Pharmaceuticals, Inc. 3′,5′-cyclic phosphoramidate prodrugs for HCV infection
EA027929B1 (ru) 2012-05-25 2017-09-29 Янссен Сайенсиз Айрлэнд Юси Нуклеозиды на основе урацила и спирооксетана
EP2900682A1 (fr) 2012-09-27 2015-08-05 IDENIX Pharmaceuticals, Inc. Esters et malonates de promédicaments à base de s-acyl-2-thioéthyle (sate)
US10513534B2 (en) 2012-10-08 2019-12-24 Idenix Pharmaceuticals Llc 2′-chloro nucleoside analogs for HCV infection
EP2935304A1 (fr) 2012-12-19 2015-10-28 IDENIX Pharmaceuticals, Inc. 4'-fluoro-nucléosides pour le traitement du vhc
SG11201504554UA (en) 2012-12-21 2015-07-30 Alios Biopharma Inc Substituted nucleosides, nucleotides and analogs thereof
WO2014137930A1 (fr) 2013-03-04 2014-09-12 Idenix Pharmaceuticals, Inc. Nucléosides de thiophosphate pour le traitement du vhc
EP2970358B1 (fr) 2013-03-04 2021-06-30 Idenix Pharmaceuticals LLC 3'-désoxynucléosides utilisables en vue du traitement d'une infection par le vhc
EP2970357A1 (fr) 2013-03-13 2016-01-20 IDENIX Pharmaceuticals, Inc. Pronucléotides de phosphoramidate d'acide aminé de 2'-cyano, azido et amino nucléosides pour le traitement du virus de l'hépatite c (vhc)
WO2014165542A1 (fr) 2013-04-01 2014-10-09 Idenix Pharmaceuticals, Inc. 2',4'-fluoronucléosides pour le traitement du vhc
WO2014197578A1 (fr) 2013-06-05 2014-12-11 Idenix Pharmaceuticals, Inc. 1',4'-thio nucléosides pour le traitement du virus de l'hépatite c (vhc)
WO2015017713A1 (fr) 2013-08-01 2015-02-05 Idenix Pharmaceuticals, Inc. Pronucléotides phosphoramidates avec acides aminés d de composés halogéno pyrimidines pour le traitement des hépatopathies
UA119050C2 (uk) * 2013-11-11 2019-04-25 Ґілеад Саєнсиз, Інк. ПІРОЛО[1.2-f][1.2.4]ТРИАЗИНИ, ЯКІ ВИКОРИСТОВУЮТЬСЯ ДЛЯ ЛІКУВАННЯ РЕСПІРАТОРНО-СИНЦИТІАЛЬНИХ ВІРУСНИХ ІНФЕКЦІЙ
MA39317A1 (fr) 2014-02-06 2018-01-31 Riboscience Llc Dérivés de nucléosides à substitution 4'-difluorométhyle utilisés en tant qu'inhibiteurs de la réplication de l'arn du virus de la grippe
WO2015143712A1 (fr) 2014-03-28 2015-10-01 Merck Sharp & Dohme Corp. Inhibiteurs nucléosidiques substitués en 4' de la transcriptase inverse
EP3131914B1 (fr) 2014-04-16 2023-05-10 Idenix Pharmaceuticals LLC Nucléosides méthyle ou alcynyle substitués en position 3 pour le traitement du virus de l'hépatite c
EP3137454A1 (fr) 2014-04-28 2017-03-08 Pfizer Inc. Composés hétéroaromatiques et leur utilisation en tant que ligands de la dopamine d1
TWI678369B (zh) 2014-07-28 2019-12-01 美商基利科學股份有限公司 用於治療呼吸道合胞病毒感染之噻吩並［３,２-ｄ］嘧啶、呋喃並［３,２-ｄ］嘧啶及吡咯並［３,２-ｄ］嘧啶化合物類
TWI673283B (zh) 2014-08-21 2019-10-01 美商基利科學股份有限公司 ２’－氯胺基嘧啶酮及嘧啶二酮核苷類
TWI687432B (zh) 2014-10-29 2020-03-11 美商基利科學股份有限公司 絲狀病毒科病毒感染之治療
RS62434B1 (sr) 2014-12-26 2021-11-30 Univ Emory Antivirusni n4-hidroksicitidin derivati
BR112018005048B8 (pt) 2015-09-16 2021-03-23 Gilead Sciences Inc uso de um composto antiviral ou sal do mesmo para o tratamento de uma infecção por coronaviridae
CA2998646C (fr) 2015-09-23 2021-05-18 Merck Sharp & Dohme Corp. Inhibiteurs nucleosidiques de la transcriptase inverse substitues en position 4' et preparations associees
RS65129B1 (sr) 2016-03-28 2024-02-29 Incyte Corp Jedinjenja pirolotriazina kao inhibitori tam
US10202412B2 (en) 2016-07-08 2019-02-12 Atea Pharmaceuticals, Inc. β-D-2′-deoxy-2′-substituted-4′-substituted-2-substituted-N6-substituted-6-aminopurinenucleotides for the treatment of paramyxovirus and orthomyxovirus infections
EP4331677A3 (fr) 2017-03-14 2024-05-29 Gilead Sciences, Inc. Procédés de traitement d'infections à coronavirus félin
US10836787B2 (en) 2017-05-01 2020-11-17 Gilead Sciences, Inc. Crystalline forms of (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5- (4-aminopyrrolo[2,1-f] [1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)amino)propanoate
WO2019014247A1 (fr) 2017-07-11 2019-01-17 Gilead Sciences, Inc. Compositions comprenant un inhibiteur d'arn polymérase et de la cyclodextrine pour le traitement d'infections virales
CN111372592A (zh) 2017-12-07 2020-07-03 埃默里大学 N4-羟基胞苷及衍生物和与其相关的抗病毒用途
US11040975B2 (en) 2017-12-08 2021-06-22 Merck Sharp & Dohme Corp. Carbocyclic nucleoside reverse transcriptase inhibitors
CA3163424A1 (fr) 2020-01-27 2021-08-05 Gilead Sciences, Inc. Procedes de traitement d'infections par sras cov-2
CN113214262B (zh) * 2020-02-05 2023-07-07 华创合成制药股份有限公司 一种含有胍基的化合物及其制备方法和用途
CN113214334A (zh) * 2020-02-05 2021-08-06 华创合成制药股份有限公司 用于治疗病毒感染的化合物及其制备方法和用途
TWI791193B (zh) 2020-02-18 2023-02-01 美商基利科學股份有限公司 抗病毒化合物
JP7429799B2 (ja) 2020-02-18 2024-02-08 ギリアード サイエンシーズ， インコーポレイテッド 抗ウイルス化合物
TW202322824A (zh) 2020-02-18 2023-06-16 美商基利科學股份有限公司 抗病毒化合物
TWI775313B (zh) 2020-02-18 2022-08-21 美商基利科學股份有限公司 抗病毒化合物
JP7554841B2 (ja) 2020-03-12 2024-09-20 ギリアード サイエンシーズ， インコーポレイテッド １’－シアノヌクレオシドを調製する方法
US11701372B2 (en) 2020-04-06 2023-07-18 Gilead Sciences, Inc. Inhalation formulations of 1'-cyano substituted carba-nucleoside analogs
KR20230018473A (ko) 2020-05-29 2023-02-07 길리애드 사이언시즈, 인코포레이티드 렘데시비르 치료 방법
CN115996928A (zh) 2020-06-24 2023-04-21 吉利德科学公司 1’-氰基核苷类似物及其用途
CN111793101B (zh) * 2020-07-17 2022-09-30 四川大学 C-核苷化合物的合成方法
AU2021331214B2 (en) 2020-08-27 2024-01-04 Gilead Sciences, Inc. Compounds and methods for treatment of viral infections
EP4323362A1 (fr) 2021-04-16 2024-02-21 Gilead Sciences, Inc. Procédés de préparation de carbanucléosides à l'aide d'amides
US12116380B2 (en) 2021-08-18 2024-10-15 Gilead Sciences, Inc. Phospholipid compounds and methods of making and using the same
MX2024002116A (es) 2021-08-20 2024-03-06 Shionogi & Co Derivados de nucleosido y profarmacos de los mismos que tienen accion inhibidora del crecimiento viral.
CN118613472A (zh) * 2022-01-31 2024-09-06 新前沿生物公司 基于烟酸酯和烟酰胺核苷的化合物及其衍生物
TW202400185A (zh) 2022-03-02 2024-01-01 美商基利科學股份有限公司 用於治療病毒感染的化合物及方法
CN117126199A (zh) * 2023-05-17 2023-11-28 江西师范大学 一种氟代瑞德西韦合成方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002032920A2 (fr) * 2000-10-18 2002-04-25 Pharmasset Limited Nucleosides modifies pour traiter des infections virales et une proliferation cellulaire anormale
WO2003062257A1 (fr) * 2002-01-17 2003-07-31 Ribapharm Inc. Analogues de nucleosides desazapurine et utilisation de ceux-ci en tant qu'agents therapeutiques
WO2010002877A2 (fr) * 2008-07-03 2010-01-07 Biota Scientific Management Nucléosides bicycliques et nucléotides convenant comme agents thérapeutiques

Family Cites Families (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3361306A (en) 1966-03-31 1968-01-02 Merck & Co Inc Aerosol unit dispensing uniform amounts of a medically active ingredient
US3565070A (en) 1969-02-28 1971-02-23 Riker Laboratories Inc Inhalation actuable aerosol dispenser
FR2224175B1 (fr) 1973-04-04 1978-04-14 Isf Spa
US4069819A (en) 1973-04-13 1978-01-24 Societa Farmaceutici S.P.A. Inhalation device
IT1017153B (it) 1974-07-15 1977-07-20 Isf Spa Apparecchio per inalazioni
SE438261B (sv) 1981-07-08 1985-04-15 Draco Ab Anvendning i dosinhalator av ett perforerat membran
US4816570A (en) 1982-11-30 1989-03-28 The Board Of Regents Of The University Of Texas System Biologically reversible phosphate and phosphonate protective groups
US4805811A (en) 1985-03-29 1989-02-21 Aktiebolaget Draco Dosage device
SE448277B (sv) 1985-04-12 1987-02-09 Draco Ab Indikeringsanordning vid en doseringsanordning for lekemedel
US4968788A (en) 1986-04-04 1990-11-06 Board Of Regents, The University Of Texas System Biologically reversible phosphate and phosphonate protective gruops
IT1228459B (it) 1989-02-23 1991-06-19 Phidea S R L Inalatore con svuotamento regolare e completo della capsula.
US4955371A (en) 1989-05-08 1990-09-11 Transtech Scientific, Inc. Disposable inhalation activated, aerosol device for pulmonary medicine
DK0533833T3 (da) 1990-06-13 1996-04-22 Arnold Glazier Phosphorprolægemidler
EP0481214B1 (fr) 1990-09-14 1998-06-24 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Pro-médicaments dérivés de phosphonates
DE69233690T2 (de) 1991-07-02 2008-01-24 Nektar Therapeutics, San Carlos Abgabevorrichtung für nebelförmige Medikamente
US5261538A (en) 1992-04-21 1993-11-16 Glaxo Inc. Aerosol testing method
US5785049A (en) 1994-09-21 1998-07-28 Inhale Therapeutic Systems Method and apparatus for dispersion of dry powder medicaments
US5388572A (en) 1993-10-26 1995-02-14 Tenax Corporation (A Connecticut Corp.) Dry powder medicament inhalator having an inhalation-activated piston to aerosolize dose and deliver same
US5522385A (en) 1994-09-27 1996-06-04 Aradigm Corporation Dynamic particle size control for aerosolized drug delivery
US5544647A (en) 1994-11-29 1996-08-13 Iep Group, Inc. Metered dose inhalator
US5622163A (en) 1994-11-29 1997-04-22 Iep Group, Inc. Counter for fluid dispensers
US6312662B1 (en) 1998-03-06 2001-11-06 Metabasis Therapeutics, Inc. Prodrugs phosphorus-containing compounds
US6116234A (en) 1999-02-01 2000-09-12 Iep Pharmaceutical Devices Inc. Metered dose inhaler agitator
DE19912636A1 (de) 1999-03-20 2000-09-21 Aventis Cropscience Gmbh Bicyclische Heterocyclen, Verfahren zu ihrer Herstellung und ihre Verwendung als Herbizide und pharmazeutische Mittel
NZ578556A (en) 2007-01-12 2012-04-27 Biocryst Pharm Inc Antiviral nucleoside analogs
ES2393038T3 (es) 2007-05-10 2012-12-18 Biocryst Pharmaceuticals, Inc. Compuestos de tretrahidrofuro[3,4-D]dioxolano para su utlilización en el tratamiento de las infecciones víricas y del cáncer
ES2398684T3 (es) 2008-04-23 2013-03-21 Gilead Sciences, Inc. Análogos de carbanucleósido para el tratamiento antiviral
US7973013B2 (en) * 2009-09-21 2011-07-05 Gilead Sciences, Inc. 2'-fluoro substituted carba-nucleoside analogs for antiviral treatment
EP2480552B1 (fr) * 2009-09-21 2016-11-09 Gilead Sciences, Inc. Analogues de carbanucléoside 2'-fluoro-substitués pour traitement antiviral

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002032920A2 (fr) * 2000-10-18 2002-04-25 Pharmasset Limited Nucleosides modifies pour traiter des infections virales et une proliferation cellulaire anormale
WO2003062257A1 (fr) * 2002-01-17 2003-07-31 Ribapharm Inc. Analogues de nucleosides desazapurine et utilisation de ceux-ci en tant qu'agents therapeutiques
WO2010002877A2 (fr) * 2008-07-03 2010-01-07 Biota Scientific Management Nucléosides bicycliques et nucléotides convenant comme agents thérapeutiques

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
HSING-PANG HSIEH ET AL: "Strategies of Development of Antiviral Agents Directed Against Influenza Virus Replication", CURRENT PHARMACEUTICAL DESIGN, vol. 13, no. 34, 1 December 2007 (2007-12-01), pages 3531 - 3542, XP055093630, ISSN: 1381-6128, DOI: 10.2174/138161207782794248 *
PATIL S A ET AL: "4-Aza-7,9-dideazaadenosine, a new cytotoxic synthetic C-nucleoside analogue of adenosine", TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 35, 1 January 1994 (1994-01-01), pages 5339 - 5342, XP002484790, ISSN: 0040-4039, DOI: 10.1016/S0040-4039(00)73494-0 *
See also references of WO2012037038A1 *
TUTTLE J V ET AL: "Purine 2'Deoxy-2'-fluororibosides as antiinfluenza agents", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, vol. 36, 1 January 1993 (1993-01-01), pages 119 - 125, XP002537133, ISSN: 0022-2623, DOI: 10.1021/JM00053A015 *
WEI-DONG MENG ET AL: "Fluorinated Nucleosides as Antiviral and Antitumor Agents", CURRENT TOPICS IN MEDICINAL CHEMISTRY, vol. 6, no. 14, 1 July 2006 (2006-07-01), NL, pages 1499 - 1528, XP055213442, ISSN: 1568-0266, DOI: 10.2174/156802606777951082 *

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CN103153314A (zh) 2013-06-12
CA2807584A1 (fr) 2012-03-22
US20140200188A1 (en) 2014-07-17
US20120107274A1 (en) 2012-05-03
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AU2011302310A1 (en) 2013-02-28
AR082960A1 (es) 2013-01-23
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EA201390142A1 (ru) 2013-09-30
BR112013005888A2 (pt) 2016-05-10

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